Marco Marcia

Marco Marcia spent years working out how RNA splices itself, one of the fundamental reactions of life. He now uses that understanding to design molecules that shut the process down in fungal pathogens.

Associate Professor

Department of Cell and Molecular Biology at Uppsala University

marco.marcia@icm.uu.se

Marco's research group website

Research focus and interests

Targeting fungal splicing machineries (group II introns) with small molecules, as a novel antimicrobial therapeutic strategy
Catalysis and folding dynamics of group II intron splicing by RNA cryoEM
Method development for RNA cryoEM sample preparation and data acquisition
Support to AI-driven RNA structural predictions
Biological mechanism and therapeutic roles of human lncRNAs in cancer and neurodevelopment

Research expertise and methodologies

RNA biochemistry
RNA cryoEM and X-ray crystallography
RNA chemical probing (SHAPE-MaP)
functional assays in vitro and in yeast and mammalian cells

Ongoing research projects

Through high-resolution structural studies (X-ray crystallography, cryo-EM), coupled to enzymatic assays, biochemical characterization and computational calculations, we have elucidated the molecular mechanism of one of the most fundamental reaction in life, splicing. We have specifically determined the mechanism of catalysis, the principles of folding, and the molecular bases for inhibition of bacterial and organellar self-splicing ribozymes by small molecules. Supported by evolutionary conservation, our study also provides near atomic clues to understand the mechanism of nuclear splicing, by the spliceosome. Now, our RNA-directed drug discovery effort shows how splicing can be regulated pharmacologically which is relevant for the treatment of microbial (fungal) infections as well as of cancer and neurodevelopmental and congenital disorders.

Key Publications

Jadhav S., Maiorca M., Manigrasso J., Muscat S., Mulvaney T., De Vivo M., Topf M., Marcia M. Dynamic assembly of a large multidomain ribozyme visualized by cryo-electron microscopy. Nature Communications (2025), 16:10195. https://doi.org/10.1038/s41467-025-65502-8
Silvestri I., Manigrasso J., Andreani A., Brindani N., De Vivo M., Marcia M. Targeting the conserved active site of splicing machines with specific and selective small molecule modulators. Nature Communications (2024), 15:4980. https://doi.org/10.1038/s41467-024-48697-0
Martin W.J., Grandi P., Marcia M. Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds. Trends in Pharmacological Sciences (2021), 42:758–771. https://doi.org/10.1016/j.tips.2021.06.001
Zhao C., Rajashankar K., Marcia M., Pyle A.M. Crystal structure of group II intron domain 1 reveals a template for RNA assembly. Nature Chemical Biology (2015), 11:967–972. https://doi.org/10.1038/nchembio.1949
Marcia M., Pyle A.M. Visualizing group II intron catalysis through the stages of splicing. Cell (2012), 151:497–507. https://doi.org/10.1016/j.cell.2012.09.033

Publications

A group II intron-encoded protein interacts with the cellular replicative machinery through the β-sliding clamp.

García-Rodríguez, Fernando M; Neira, José L; Marcia, Marco; Molina-Sánchez, María D et al.

Part of Nucleic Acids Research, p. 7605-7617, 2019
- DOI for A group II intron-encoded protein interacts with the cellular replicative machinery through the β-sliding clamp.
A new structure-based classification of sulfide: quinone oxidoreductases.

Marcia, Marco; Ermler, Ulrich; Peng, Guohong; Michel, Hartmut

Part of Proteins, p. 1073-83, 2010
- DOI for A new structure-based classification of sulfide: quinone oxidoreductases.
A Transient and Flexible Cation-π Interaction Promotes Hydrolysis of Nucleic Acids in DNA and RNA Nucleases.

Genna, Vito; Marcia, Marco; De Vivo, Marco

Part of Journal of the American Chemical Society, p. 10770-10776, 2019
- DOI for A Transient and Flexible Cation-π Interaction Promotes Hydrolysis of Nucleic Acids in DNA and RNA Nucleases.
ADAR RNA editing on antisense RNAs results in apparent U-to-C base changes on overlapping sense transcripts.

Pecori, Riccardo; Chillón, Isabel; Lo Giudice, Claudio; Arnold, Annette et al.

Part of Frontiers in cell and developmental biology, p. 1080626, 2022
- DOI for ADAR RNA editing on antisense RNAs results in apparent U-to-C base changes on overlapping sense transcripts.
biGMamAct: efficient CRISPR/Cas9-mediated docking of large functional DNA cargoes at the ACTB locus

Pelosse, Martin; Marcia, Marco

Part of SYNTHETIC BIOLOGY, 2025
- DOI for biGMamAct: efficient CRISPR/Cas9-mediated docking of large functional DNA cargoes at the ACTB locus
- Download full text (pdf) of biGMamAct: efficient CRISPR/Cas9-mediated docking of large functional DNA cargoes at the ACTB locus
Characterizing a monotopic membrane enzyme. Biochemical, enzymatic and crystallization studies on Aquifex aeolicus sulfide: quinone oxidoreductase.

Marcia, Marco; Langer, Julian D; Parcej, David; Vogel, Vitali et al.

Part of Biochimica et Biophysica Acta, p. 2114-23, 2010
- DOI for Characterizing a monotopic membrane enzyme. Biochemical, enzymatic and crystallization studies on Aquifex aeolicus sulfide: quinone oxidoreductase.
Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery

Manigrasso, Jacopo; Marcia, Marco; De Vivo, Marco

Part of Chem, p. 2965-2988, 2021
- DOI for Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery
Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway.

Uroda, Tina; Anastasakou, Eleni; Rossi, Annalisa; Teulon, Jean-Marie et al.

Part of Molecular Cell, p. 982-995000000000, 2019
- DOI for Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway.
Controlled dynamic remodeling of the spliceosome active site enables the first step of splicing

Martino, Gianfranco; Manigrasso, Jacopo; La Sala, Giuseppina; Marcia, Marco et al.

Part of Proceedings of the National Academy of Sciences of the United States of America, 2026
- DOI for Controlled dynamic remodeling of the spliceosome active site enables the first step of splicing
- Download full text (pdf) of Controlled dynamic remodeling of the spliceosome active site enables the first step of splicing
Crystal structure of group II intron domain 1 reveals a template for RNA assembly.

Zhao, Chen; Rajashankar, Kanagalaghatta R; Marcia, Marco; Pyle, Anna Marie

Part of Nature Chemical Biology, p. 967-72, 2015
- DOI for Crystal structure of group II intron domain 1 reveals a template for RNA assembly.
Dynamic assembly of a large multidomain ribozyme visualized by cryo-electron microscopy

Jadhav, Shekhar; Maiorca, Mauro; Manigrasso, Jacopo; Saha, Spandan et al.

Part of Nature Communications, 2025
- DOI for Dynamic assembly of a large multidomain ribozyme visualized by cryo-electron microscopy
- Download full text (pdf) of Dynamic assembly of a large multidomain ribozyme visualized by cryo-electron microscopy
Finding the Ion in the RNA-Stack: Can Computational Models Accurately Predict Key Functional Elements in Large Macromolecular Complexes?

Marcia, Marco; Manigrasso, Jacopo; De Vivo, Marco

Part of Journal of Chemical Information and Modeling, p. 2511-2515, 2021
- DOI for Finding the Ion in the RNA-Stack: Can Computational Models Accurately Predict Key Functional Elements in Large Macromolecular Complexes?
Functional Relevance of CASP16 Nucleic Acid Predictions as Evaluated by Structure Providers

Kretsch, Rachael C.; Albrecht, Reinhard; Andersen, Ebbe S.; Chen, Hsuan-Ai et al.

Part of Proteins, p. 51-78, 2026
- DOI for Functional Relevance of CASP16 Nucleic Acid Predictions as Evaluated by Structure Providers
- Download full text (pdf) of Functional Relevance of CASP16 Nucleic Acid Predictions as Evaluated by Structure Providers
G·U base pairing motifs in long non-coding RNAs.

Sabalette, Karina Belen; Makarova, Liubov; Marcia, Marco

Part of Biochimie, p. 123-140, 2023
- DOI for G·U base pairing motifs in long non-coding RNAs.
HOTAIR forms an intricate and modular secondary structure.

Somarowthu, Srinivas; Legiewicz, Michal; Chillón, Isabel; Marcia, Marco et al.

Part of Molecular Cell, p. 353-61, 2015
- DOI for HOTAIR forms an intricate and modular secondary structure.
Identification of high-confidence RNA regulatory elements by combinatorial classification of RNA-protein binding sites.

Li, Yang Eric; Xiao, Mu; Shi, Binbin; Yang, Yu-Cheng T et al.

Part of Genome Biology, p. 169, 2017
- DOI for Identification of high-confidence RNA regulatory elements by combinatorial classification of RNA-protein binding sites.
Ion binding and internal hydration in the multidrug resistance secondary active transporter NorM investigated by molecular dynamics simulations.

Vanni, Stefano; Campomanes, Pablo; Marcia, Marco; Rothlisberger, Ursula

Part of Biochemistry, p. 1281-7, 2012
- DOI for Ion binding and internal hydration in the multidrug resistance secondary active transporter NorM investigated by molecular dynamics simulations.
Native Purification and Analysis of Long RNAs.

Chillón, Isabel; Marcia, Marco; Legiewicz, Michal; Liu, Fei et al.

Part of Methods in Enzymology, p. 3-37, 2015
- DOI for Native Purification and Analysis of Long RNAs.
Noncoding RNAs: biology and applications-a Keystone Symposia report.

Cable, Jennifer; Heard, Edith; Hirose, Tetsuro; Prasanth, Kannanganattu V et al.

Part of Annals of the New York Academy of Sciences, p. 118-141, 2021
- DOI for Noncoding RNAs: biology and applications-a Keystone Symposia report.
Now on display: a gallery of group II intron structures at different stages of catalysis.

Marcia, Marco; Somarowthu, Srinivas; Pyle, Anna Marie

Part of Mobile DNA, p. 14, 2013
- DOI for Now on display: a gallery of group II intron structures at different stages of catalysis.
On the Power and Challenges of Atomistic Molecular Dynamics to Investigate RNA Molecules

Muscat, Stefano; Martino, Gianfranco; Manigrasso, Jacopo; Marcia, Marco et al.

Part of Journal of Chemical Theory and Computation, p. 6992-7008, 2024
- DOI for On the Power and Challenges of Atomistic Molecular Dynamics to Investigate RNA Molecules
PICKScreens, A New Database for the Comparison of Crystallization Screens for Biological Macromolecules

Hedderich, Tanja; Marcia, Marco; Köpke, Jürgen; Michel, Hartmut

Part of Crystal Growth & Design, p. 488-491, 2010
- DOI for PICKScreens, A New Database for the Comparison of Crystallization Screens for Biological Macromolecules
Principles of ion recognition in RNA: insights from the group II intron structures.

Marcia, Marco; Pyle, Anna Marie

Part of RNA, p. 516-27, 2014
- DOI for Principles of ion recognition in RNA: insights from the group II intron structures.
Production of fully assembled and active Aquifex aeolicus F1FO ATP synthase in Escherichia coli.

Zhang, Chunli; Allegretti, Matteo; Vonck, Janet; Langer, Julian D et al.

Part of Biochimica et Biophysica Acta, p. 34-40, 2014
- DOI for Production of fully assembled and active Aquifex aeolicus F1FO ATP synthase in Escherichia coli.
Role of the N-terminal signal peptide in the membrane insertion of Aquifex aeolicus F1F0 ATP synthase c-subunit.

Zhang, Chunli; Marcia, Marco; Langer, Julian D; Peng, Guohong et al.

Part of The FEBS Journal, p. 3425-35, 2013
- DOI for Role of the N-terminal signal peptide in the membrane insertion of Aquifex aeolicus F1F0 ATP synthase c-subunit.
Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds.

Martin, William J; Grandi, Paola; Marcia, Marco

Part of TIPS - Trends in Pharmacological Sciences, p. 758-771, 2021
- DOI for Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds.
Second-Shell Basic Residues Expand the Two-Metal-Ion Architecture of DNA and RNA Processing Enzymes.

Genna, Vito; Colombo, Matteo; De Vivo, Marco; Marcia, Marco

Part of Structure, p. 40-5000, 2018
- DOI for Second-Shell Basic Residues Expand the Two-Metal-Ion Architecture of DNA and RNA Processing Enzymes.
Solving nucleic acid structures by molecular replacement: examples from group II intron studies.

Marcia, Marco; Humphris-Narayanan, Elisabeth; Keating, Kevin S; Somarowthu, Srinivas et al.

Part of Acta Crystallographica Section D, p. 2174-85, 2013
- DOI for Solving nucleic acid structures by molecular replacement: examples from group II intron studies.
Targeting the conserved active site of splicing machines with specific and selective small molecule modulators.

Silvestri, Ilaria; Manigrasso, Jacopo; Andreani, Alessandro; Brindani, Nicoletta et al.

Part of Nature Communications, p. 4980, 2024
- DOI for Targeting the conserved active site of splicing machines with specific and selective small molecule modulators.
The molecular structure of long non-coding RNAs: emerging patterns and functional implications.

Chillón, Isabel; Marcia, Marco

Part of Critical reviews in biochemistry and molecular biology, p. 662-690, 2020
- DOI for The molecular structure of long non-coding RNAs: emerging patterns and functional implications.
The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis.

Marcia, Marco

Part of Current Opinion in Oncology, p. 141-147, 2022
- DOI for The multiple molecular dimensions of long noncoding RNAs that regulate gene expression and tumorigenesis.
The new world of RNA diagnostics and therapeutics.

Blandino, Giovanni; Dinami, Roberto; Marcia, Marco; Anastasiadou, Eleni et al.

Part of Journal of Experimental & Clinical Cancer Research, p. 189, 2023
- DOI for The new world of RNA diagnostics and therapeutics.
The structure of Aquifex aeolicus sulfide: quinone oxidoreductase, a basis to understand sulfide detoxification and respiration.

Marcia, Marco; Ermler, Ulrich; Peng, Guohong; Michel, Hartmut

Part of Proceedings of the National Academy of Sciences of the United States of America, p. 9625-30, 2009
- DOI for The structure of Aquifex aeolicus sulfide: quinone oxidoreductase, a basis to understand sulfide detoxification and respiration.
Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform.

Colombo, Matteo; Pessey, Ombeline; Marcia, Marco

Part of FEBS Letters, p. 1837-1848, 2019
- DOI for Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform.
Using Molecular Replacement Phasing to Study the Structure and Function of RNA.

Marcia, Marco

Part of Methods in Molecular Biology, p. 233-57, 2016
- DOI for Using Molecular Replacement Phasing to Study the Structure and Function of RNA.
Visualizing group II intron catalysis through the stages of splicing.

Marcia, Marco; Pyle, Anna Marie

Part of Cell, p. 497-507, 2012
- DOI for Visualizing group II intron catalysis through the stages of splicing.
Visualizing group II intron dynamics between the first and second steps of splicing.

Manigrasso, Jacopo; Chillón, Isabel; Genna, Vito; Vidossich, Pietro et al.

Part of Nature Communications, p. 2837, 2020
- DOI for Visualizing group II intron dynamics between the first and second steps of splicing.
Visualizing the functional 3D shape and topography of long noncoding RNAs by single-particle atomic force microscopy and in-solution hydrodynamic techniques.

Uroda, Tina; Chillón, Isabel; Annibale, Paolo; Teulon, Jean-Marie et al.

Part of Nature Protocols, p. 2107-2139, 2020
- DOI for Visualizing the functional 3D shape and topography of long noncoding RNAs by single-particle atomic force microscopy and in-solution hydrodynamic techniques.